Case Report: Efficacy of Reduced Doses of Asfotase Alfa Replacement Therapy in an Infant With Hypophosphatasia Who Lacked Severe Clinical Symptoms

BackgroundHypophosphatasia is a rare bone disease characterized by impaired bone mineralization and low alkaline phosphatase activity. Here, we describe the course of bone-targeted enzyme replacement therapy with asfotase alpha for a female infant patient with hypophosphatasia who lacked apparent severe clinical symptoms.Case presentationThe patient exhibited low serum alkaline phosphatase (60 U/L; age-matched reference range, 520–1,580) in a routine laboratory test at birth. Further examinations revealed skeletal demineralization and rachitic changes, as well as elevated levels of serum calcium (2.80 mmol/L; reference range, 2.25–2.75 mmol/L) and ionic phosphate (3.17 mmol/L; reference range, 1.62–2.48 mmol/L), which are typical features in patients with hypophosphatasia. Sequencing analysis of the tissue-nonspecific alkaline phosphatase (TNSALP) gene identified two pathogenic mutations: c.406C>T, p.Arg136Cys and c.979T>C, p.Phe327Leu. Thus, the patient was diagnosed with hypophosphatasia. At the age of 37 days, she began enzyme replacement therapy using asfotase alpha at the standard dose of 6 mg/kg/week. Initial therapy from the age of 37 days to the age of 58 days substantially improved rickets signs in the patient; it also provided immediate normalization of serum calcium and ionic phosphate levels. However, serum ionic phosphate returned to a high level (2.72 mmol/L), which was presumed to be a side effect of asfotase alpha. Thus, the patient’s asfotase alfa treatment was reduced to 2 mg/kg/week, which allowed her to maintain normal or near normal skeletal features thereafter, along with lowered serum ionic phosphate levels. Because the patient exhibited slight distal metaphyseal demineralization in the knee at the age of 2 years and 6 months, her asfotase alfa treatment was increased to 2.4 mg/kg/week. No signs of deterioration in bone mineralization were observed thereafter. At the age of 3 years, the patient’s motor and psychological development both appeared normal, compared with children of similar age.ConclusionThis is the first report in which reduced doses of asfotase alfa were administered to an infant patient with hypophosphatasia who lacked apparent severe clinical symptoms. The results demonstrate the potential feasibility of a tailored therapeutic option based on clinical severity in patients with hypophosphatasia.

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Pediatric hypophosphatasia: a retrospective single-centre chart review of 50 children

10.21203/rs.2.22056/v1 ◽

2020 ◽

Author(s):

Marius Vogt ◽

Hermann Girschick ◽

Tilmann Schweitzer ◽

Clemens Benoit ◽

Annette Holl-Wieden ◽

...

Keyword(s):

Alkaline Phosphatase ◽

Natural History ◽

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Chart Review ◽

Clinical Symptoms ◽

Single Centre ◽

Enzyme Replacement ◽

Asfotase Alfa ◽

Diagnostic Time

Abstract Background: Hypophosphatasia (HPP) is a rare, inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the tissue-nonspecific alkaline phosphatase TNAP (ORPHA 436). Its clinical presentation is highly heterogeneous with a remarkably wide-ranging severity. HPP affects patients of all ages. Therefore, diagnosis is often difficult and delayed. To improve the understanding of HPP in children and in order to shorten the diagnostic time span in the future we studied the natural history of the disease in our large cohort of pediatric patients. In light of the enzyme replacement therapy (Asfotase alfa, a recombinant mineral-targeted TNAP), HPP patients may benefit from early and patient severity orientated calculated treatment in the course of the disease. Methods: This single centre retrospective chart review included longitudinal data from 50 patients with HPP diagnosed and followed at the University Children`s Hospital Wuerzburg, Germany over the last 25 years. Results: The cohort comprises 4 (8%) perinatal, 17 (34%) infantile and 29 (58%) childhood onset HPP patients. Two patients were deceased at the time of data collection. Diagnosis was based on available characteristic clinical symptoms (in 88%), low alkaline phosphatase (AP) activity (in 96%), accumulating substrates of AP (in 58%) and X-ray findings (in 48%). Genetic analysis was performed in 48 patients (35 compound heterozygous, 11 heterozygous, 2 homozygous mutations per patient), allowing investigations on genotype-phenotype correlations. Based on anamnestic data, median age at first clinical symptoms was 3.5 months (min. 0, max. 107), while median time to diagnosis was 13 months (min. 0, max. 103). Common symptoms included: impairment of motor skills (78%), impairment of mineralization (72%), premature loss of teeth (64%), musculoskeletal pain and craniosynostosis (each 64%) and failure to thrive (62%). Up to now 20 patients started medical treatment with Asfotase alfa. Conclusions: Reported findings support the clinical perception of HPP being a chronic multi-systemic disease with often delayed diagnosis. Our natural history information provides detailed insights into the prevalence of different symptoms, which can help to improve and shorten diagnostics and thereby lead to an optimised medical care, especially with promising therapeutic options like enzyme-replacement-therapy with Asfotase alfa in mind.

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Hypophosphatasia Misdiagnosed as Osteoporosis in a Young Girl

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.409 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A201-A202

Author(s):

Tiffany Tsang ◽

Maya P Raghuwanshi

Keyword(s):

Alkaline Phosphatase ◽

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Muscular Atrophy ◽

Mineral Metabolism ◽

Pulmonary Complications ◽

Inherited Disease ◽

Inorganic Pyrophosphate ◽

Enzyme Replacement ◽

Asfotase Alfa

Abstract Introduction: Hypophosphatasia (HPP) is a rare inherited disease of mineral metabolism characterized by low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNALP), which causes an inability to liberate inorganic phosphate for hydroxyapatite crystal propagation as well as toxic accumulation of inorganic pyrophosphate, pyridoxal-5’-phosphate and urinary phosphoethanolamine. It has a prevalence of 1/100,000 to 1/900,000, although milder forms have an estimated prevalence of 1/6,370. Variable mutations in TNALP cause clinical expressions ranging from a severe perinatal form, which is often fatal after birth from pulmonary complications, to an infantile form, which can cause vitamin B6-responsive seizures, to an asymptomatic adult form. Case: A 27-year-old, ventilator-dependent female with osteoporosis, hypothyroidism, cerebral palsy with previous spinal fusion, seizure disorder and nephrocalcinosis presented with surgical site infection from a right femur ORIF she underwent a month ago. She had a history of microfractures and low-impact fractures of both femurs requiring several surgeries. Osteoporosis was diagnosed at age 5 and she had been on Fosamax ever since. She did not meet any developmental milestones as a baby and never reached menarche. Various diagnoses by multiple specialists did not fully explain her clinical presentation. Her medications included alendronate 5 mg, calcium carbonate 600 mg, ergocalciferol 400 U and levothyroxine 50 mcg. Physical exam showed poor dentition, a misshapen skull and bowed legs with contractures of her extremities. Her labs revealed Ca 9.1 mg/dL (8.4–10.2 mg/dL), albumin 3.2 gm/dL (3.5–5.2 gm/dL), phosphorus 5.1 mg/dL (2.5–4.5 mg/dL), alkaline phosphatase 32 U/L (35–105 U/L), PTH 28 pg/mL (15–65 pg/mL), vitamin D 33.5 ng/mL (30–100 ng/mL), C-telopeptide 509 pg/mL (34–635 pg/mL). A right knee X-Ray reported diffusely gracile and demineralized bones with muscular atrophy. She recently transitioned care from a pediatric endocrinologist to an adult endocrinologist, who tested her positive for heterozygous ALPL pathogenic variant hypophosphatasia and was considering her for asfotase alfa enzyme replacement therapy. Discussion: Our patient had infantile HPP, but due to misdiagnosis as osteoporosis, she was inappropriately treated with a bisphosphate for over 20 years. Treatment of HPP had been supportive until the approval of asfotase alfa (Strensiq) in October 2015. It is a bone-targeted human recombinant enzyme replacement therapy approved for infantile- and juvenile-onset HPP and has been shown to decrease mortality from 73% to 16% at age 5. With improvement in life-sustaining technology, more HPP patients are able to survive into adulthood. Awareness of the complex and polymorphic presentation of HPP by adult endocrinologists is paramount for accurate diagnosis, thus avoiding inappropriate treatments.

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ADULT-ONSET HYPOPHOSPHATASIA: BEFORE AND AFTER TREATMENT WITH ASFOTASE ALFA

AACE Clinical Case Reports ◽

10.4158/accr-2019-0143 ◽

2019 ◽

Vol 5 (6) ◽

pp. e344-e348

Author(s):

Angela L. Magdaleno ◽

Sonum Singh ◽

Sandhya Venkataraman ◽

Gretchen A. Perilli ◽

Ya-Yu Lee

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Laboratory Data ◽

Whole Body ◽

Adult Onset ◽

Enzyme Replacement ◽

Asfotase Alfa ◽

Focal Uptake ◽

Patient Reported ◽

Before And After

Objective: To review the diagnosis and clinical course of a woman with hypophosphatasia who is being treated with newly approved enzyme replacement therapy, asfotase alfa. Methods: Clinical and laboratory data are presented. Results: This is a unique report of a woman with debilitating adult-onset hypophosphatasia who was successfully diagnosed with low alkaline phosphatase (ALP) levels and elevated vitamin B6 levels. Treatment with asfotase alfa resolved her chronic bony pain symptoms and quadrupled her daily pedometer step count. Furthermore, whole body scans before and after treatment showed less focal uptake overall, suggesting fracture healing after enzyme replacement therapy. Conclusion: Improvement in patient reported symptoms, daily pedometer count, and whole body scans was noted after treatment of adult-onset hypophosphatasia with asfotase alfa enzyme replacement therapy. The significance of increased ALP levels after treatment is currently unknown.

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Could Enzyme Replacement Therapy for Long Time Normalize Chitotriosidase Activity in Type 1 Gaucher Disease?.

Blood ◽

10.1182/blood.v104.11.3802.3802 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3802-3802

Author(s):

Pilar Giraldo ◽

Pilar Alfonso ◽

Juan Perez-Calvo ◽

Manuel Giralt

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Bone Disease ◽

Clinical Symptoms ◽

Analytical Data ◽

Enzyme Replacement ◽

Group A ◽

Group B

Abstract Background: Extreme elevations of plasma chitotriosidase (CT) are observed in Gaucher’s disease (GD) patients. This enzyme has been considered as a response marker to enzyme replacement therapy (ERT). It has been previously described the normalization of enzymatic activity only in patients who have been treated by bone marrow transplantation (Young E et al, 1997). It is widely accepted that GD subjects receiving ERT show improvements in clinical symptoms and regression of signs of disease, such as disappearance or reduction of visceral enlargement, normalized haematological parameters and skeletal improvement and also reduce the CT activity values, but these do not actually reach a normal range. Surprisingly, in the follow-up of patients included in the Spanish Gaucher Registry, some cases showed normalization of their CT activity after several years under therapy. The purpose of this study is to analyze the clinical, analytical and genotype characteristics of type 1 GD patients that have normalized their CT activity and to compare with the rest of patients under ERT for same period of follow-up. Patients and Methods: We have studied a cohort of 64 type 1 GD patients receiving ERT. We observed 20 GD patients who reach a normal CT activity range (CT activity < 200 nmol/mL.h) under therapy 2–7 years (group A) and 44 GD patients whose CT activity maintained increased under therapy 2–10 years (group B). Clinical and analytical data have been obtained from Spanish GD registry. Assessment of response included serial measurement of haemoglobin (Hb), platelet count, liver and spleen sizes and CT activity. Plasma CT activity was measured with the fluorogenic substrate 4-methylumbelliferyl-β-D-N, N′, N″ triacetylchitotrioside. Determination of the 24-bp duplication in the CT gene was performed by PCR followed by electrophoresis of the amplified fragments. For statistical analysis we used the StatView database (version 4.5). Results: At baseline characteristics of both groups were as indicated in tables. Patients of group B had worse indicators of disease severity at baseline. SSI, percentages of bone disease and spleen removal were higher in group B than group A. In addition we found twice more heterozygous patients for 24 bp duplication of the CT gene in group A compared to group B Nevertheless, as the table shows, patients of group B received higher doses of ERT and for a longer time. Conclusion: The normalization of CT activity is infrequent in GD patients under ERT. It is influenced by CT genotype and probably by severity of disease. Clinical data Age at diagnosis Male/Female SSI Spleen removal(%) Bone disease (%) N370S Homozygous/N370S Heterozygous N: number, SSI: severity score system Analytical data Group A (n=20) 32 ± 15.0 7/13 7.6 ± 2.55 5 55 0/20 Group B (n=44) 29 ± 15.9 19/25 8.4 ± 3.15 27 66 5/39 Analytical data Hb (g/dL) Platelets x 109/L CT activity(nmol/mL.h) Heterozygous CT genotype(%) ERT Dose (Units/2 weeks) N: number; Hb: Haemoglobin; CT: chitotriosidase; ERT: Enzyme replacement theraphy Group A (n=20) 12.3 ± 1.85 72.8 ± 31.27 7,489 ± 3,751 65 34.3 ± 10.33 Group B (n=44) 11.9 ± 1.84 107.5 ± 83.85 8,459 ± 3,563 32 41.4 ± 15.08

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First two years of reimbursed enzyme replacement therapy in the treatment of Fabry disease in Poland

F1000Research ◽

10.12688/f1000research.55313.1 ◽

2021 ◽

Vol 10 ◽

pp. 841

Author(s):

Michał Nowicki ◽

Monika Komar ◽

Mariusz Kusztal ◽

Katarzyna Mizia-Stec ◽

Tomasz Liberek ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Clinical Symptoms ◽

Final Diagnosis ◽

The Body ◽

Lysosomal Storage ◽

Enzyme Replacement ◽

Number Of Patients ◽

Mean Time

Fabry disease (FD) is an ultra-rare genetic lysosomal storage disease caused by pathologic gene variants resulting in insufficient expression of α-galactosidase A. This enzyme deficiency leads to accumulation of globotriaosylceramide and globotriaosylsphingosine in plasma and in different cells throughout the body, causing major cardiovascular, renal, and nervous system complications. Until 2018, reimbursed enzyme replacement therapy (ERT) for FD was available in all European Union countries except Poland. We present the preliminary results of the first two years of reimbursed ERT in Poland. We obtained data from the seven largest academic centers in Katowice, Kraków, Wrocław, Poznań, Gdańsk, Warszawa, and Łódź. The questionnaire included the following data: number of patients treated, number of patients qualified for ERT, and patient characteristics. All centers returned completed questionnaires that included data for a total of 71 patients (28 men and 43 women) as of June 2021. Thirty-five patients with the diagnosis of FD confirmed by genetic testing (22 men and 13 women) had already qualified for reimbursed ERT. Mean (SD) age at the commencement of the ERT program was 39.6 (15.5) years (range 18-79 years). Mean time from the first clinical symptoms reported by the patients to the FD diagnosis was 21.1 (8.9) years, and the mean time from the final diagnosis of FD to the beginning of ERT was 4.7 (4.6) years. FD is still underdiagnosed in Poland. To identify undiagnosed FD patients and to ensure that patients in Poland benefit fully from ERT, implementation of an effective nationwide screening strategy and close cooperation with a network of rare disease centers is advised.

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Unsolved diagnostic issues of hypophosphatasia: Expert Council

Russian Medical Inquiry ◽

10.32364/2587-6821-2021-5-9-605-614 ◽

2021 ◽

Vol 5 (9) ◽

pp. 605-614

Author(s):

E.Yu. Zakharova ◽

◽

T.V. Varlamova ◽

S.V. Voronin ◽

N.Yu. Vlasenko ◽

...

Keyword(s):

Alkaline Phosphatase ◽

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Disease Onset ◽

Clinical Signs ◽

Orphan Diseases ◽

Loss Of Function ◽

Enzyme Replacement ◽

Mild Disease ◽

Fundamental Factor

Hypophosphatasia (HPP) is a rare hereditary metabolic disease resulting from the loss-of-function mutation in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (ALP). Clinical presentations are polymorphic and manifest themselves differently depending on the age of disease onset and severity. The occurrence of mild disease, including adult HPP, is challenging to assess due to the high heterogeneity of clinical signs and a lower diagnosis rate. Doctors’ awareness of HPP is the fundamental factor affecting its detection rate. This paper reviews the conclusions of the Expert Council on HPP diagnosis and potentialities to improve diagnosis. Ten experts from various Russian regions participated in panel sessions. Each member shared the experience and established practice on the diagnosis of orphan diseases in his/her region and gave suggestions to optimize the diagnostic approach to HPP. The result was the development of a management algorithm and routing of patients from identifying symptoms to decision making on prescribing enzyme-replacement therapy and subsequent follow-up at every level of medical care . KEYWORDS: hypophosphatasia, alkaline phosphatase, orphan diseases, ALPL, enzyme-replacement therapy, routing. FOR CITATION: Zakharova E.Yu., Varlamova T.V., Voronin S.V. et al. Unsolved diagnostic issues of hypophosphatasia: Expert Council. Russian Medical Inquiry. 2021;5(9):605–614 (in Russ.). DOI: 10.32364/2587-6821-2021-5-9-605-614.

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Enzyme replacement therapy for congenital hypophosphatasia allows for surgical treatment of related complex craniosynostosis: a case series

Neurosurgical FOCUS ◽

10.3171/2015.2.focus14847 ◽

2015 ◽

Vol 38 (5) ◽

pp. E10 ◽

Cited By ~ 8

Author(s):

Libby Kosnik-Infinger ◽

Craig Gendron ◽

Christopher B. Gordon ◽

Brian S. Pan ◽

John A. van Aalst ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Surgical Intervention ◽

Bone Mineralization ◽

Case Series ◽

Cranial Vault ◽

Loss Of Function ◽

Neurological Outcomes ◽

Enzyme Replacement ◽

Cranial Vault Remodeling

Hypophosphatasia (HPP) is a rare inherited disorder of bone metabolism that results in the loss of function of the gene coding for tissue-nonspecific alkaline phosphatase (TNSALP). Patients with HPP have defective bone mineralization as well as craniosynostosis that can be seen in the infantile and childhood forms of this disease. Traditionally, HPP has had a poor prognosis, with few children surviving to exhibit the phenotype of clinical craniosynostosis that requires surgical intervention. Here, the authors report on new advancements in enzyme replacement therapy (ERT) for children affected by HPP, allowing these patients to survive and undergo surgery to address complex craniosynostosis. The authors discuss their case series of 4 HPP patients treated at their institution with ERT who have undergone successful surgical intervention for craniosynostosis. These children had no complications related to their surgeries and exhibited decreased neurological symptoms following cranial vault remodeling. This study reveals that ERT administered either pre- or post- operatively paired with cranial vault remodeling strategies can yield improved neurological outcomes in children affected by HPP.

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Brief Clinical Report: Hypophosphatasia—Diagnostic Considerations and Treatment Outcomes in an Infant

Case Reports in Pediatrics ◽

10.1155/2018/5719761 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Sara Duffus ◽

Bradly Thrasher ◽

Ali S. Calikoglu

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Linear Growth ◽

Serum Alkaline Phosphatase ◽

Bone Mineralization ◽

Clinical Manifestations ◽

Clinical Report ◽

Radiographic Findings ◽

Enzyme Replacement ◽

Metabolic Bone Disorder

Hypophosphatasia (HPP) is a rare, inherited metabolic bone disorder characterized by low serum alkaline phosphatase activity and impaired bone mineralization. Clinical manifestations and severity of symptoms vary widely in HPP, ranging from in utero death to isolated dental manifestations in adults. Treatment with enzyme replacement therapy has been reported to improve outcomes in perinatal, infantile, and childhood forms of HPP. Here, we present a case of a boy with poor linear growth, mild limb bowing, and radiographic rickets who was diagnosed with HPP before 6 months of age. Treatment with enzyme replacement therapy was initiated at 7 months of age, after which significant improvements in radiographic findings and linear growth were demonstrated. This case highlights several important challenges in the diagnosis, classification, and management of HPP.

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Romanian Guidelines on the Diagnosis and Treatment of Exocrine Pancreatic Insufficiency

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld.2014.1121.app ◽

2015 ◽

Vol 24 (1) ◽

pp. 117-123 ◽

Cited By ~ 17

Author(s):

Cristian Gheorghe ◽

Andrada Seicean ◽

Adrian Saftoiu ◽

Marcel Tantau ◽

Eugen Dumitru ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Clinical Symptoms ◽

Pancreatic Insufficiency ◽

Pancreatic Enzyme ◽

Exocrine Pancreatic Insufficiency ◽

Exocrine Function ◽

Enzyme Replacement ◽

Pancreatic Enzyme Replacement Therapy ◽

Enteric Coated

In assessing exocrine pancreatic insufficiency (EPI), its diverse etiologies and the heterogeneous population affected should be considered. Diagnosing this condition remains a challenge in clinical practice especially for mild-to-moderate EPI, with the support of the time-consuming breath test or the coefficient of fat absorption. The fecal elastase-1 test, less precise for the diagnosis, cannot be useful for assessing treatment efficacy. Pancreatic enzyme replacement therapy (PERT) is the mainstay of treatment, whereby enteric-coated mini-microspheres are taken with every meal, in progressive doses based on an individual's weight and clinical symptoms. The main indication for PERT is chronic pancreatitis, in patients who have clinically relevant steatorrhea, abnormal pancreatic function test or abnormal function tests associated with symptoms of malabsorption such as weight loss or meteorism. While enzyme replacement therapy is not recommended in the initial stages of acute pancreatitis, pancreatic exocrine function should be monitored for at least 6-18 months. In the case of unresectable pancreatic cancer, replacement enzyme therapy helps to maintain weight and improve overall quality of life. It is also indicated in patients with celiac disease, who have chronic diarrhea (in spite of gluten-free diet), and in patients with cystic fibrosis with proven EPI.

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